Alkali-iron gluconate complexes, especially sodium iron(III)gluconate complexes as well as methods of making these compounds are known. The sodium iron(III)gluconate complex contains organically bound iron and is being used as a therapeutic agent for increasing the iron content in the blood of humans and animals. In the following the term sodium iron(III)gluconate complex is used and it is understood herein that this term generally also comprises the alkali iron(III)gluconate complexes known.
U.S. Pat. No. 6,693,211 describes a method of making sodium iron(III)gluconate complex in sucrose by treating an aqueous solution of iron chloride with an aqueous solution of a selected weak alkali at about neutral acid value (pH). The formed chloride is then separated from the formed colloidal iron(III)oxyhydroxide and reacted with sodium gluconate at elevated temperature. The sodium iron(III)gluconate complex formed is then isolated and added to an aqueous solution of sucrose to yield sodium iron gluconate complex in sucrose.
The term “iron(III)gluconate complex” which is used in the following text also includes the alkali iron(III)gluconate complexes and the preferred sodium iron(III)gluconate complex.
The methods known have major disadvantages. One of the main problems present in all the methods for making iron(III)gluconate complex, e.g. sodium iron(III)gluconate complex, is the separation of the chloride content resulting from the iron chloride, especially the separation of the counter ion formed from the iron oxyhydroxide. This content of anions is physiologically undesirable. In known methods this chloride content is separated from the slushy iron(III)oxyhydroxide. However, it is known that it is very difficult to filter freshly precipitated colloidal iron oxyhydroxide. Aged iron oxyhydroxide is easy to filter, but it cannot be used for the syntheses of physiologically active sodium iron(III)gluconate complex. Therefore the iron oxyhydroxide is being sloshed several times whereby the remaining solution is decanted. This method is technically impractical and expensive.
For producing solid sodium iron(III)gluconate complex, made as described herein before, the complex is being freeze-dried. This process generally is complicated because the chloride must be separated entirely before freeze-drying. Freeze-drying itself is a time consuming procedure consuming a lot of energy.
The method according to the present invention does not have these disadvantages. It is for example not necessary to separate the chloride content from the freshly precipitated colloidal iron oxyhydroxide. It is further possible to obtain the solid iron(III)gluconate complex by simple precipitation, for example by using an organic solvent, so that the sodium iron(III)gluconate complex made according to the present invention does not contain any undesired carrier materials or additives. Handling iron(III)gluconate complexes as a solid material is considerably easier and safer than handling a corresponding solution, as the solid material has a much smaller volume and may be transported over long distances without decomposition. The danger of introducing microbiologic impurities is very small for solid materials. It is further much easier to purify solid materials and to separate side product therefrom in comparison to purifying solutions. Therefore, it is a distinct advantage to precipitate the pure product without the addition of any auxiliary compounds. For the production of the sodium iron(III)gluconate complex in sucrose, the sodium iron(III)gluconate complex made according to the present invention is simply added to the sucrose solution; no heating is required for the formation of the sodium iron(III)gluconate/sucrose complex. After sterile filtration a preparation is obtained which is suitable for the parenteral iron therapy. For sterilizing the solution it is also possible to heat the solution using e.g. vapor sterilization. The sucrose within the sucrose solution is, according to the present invention, no integral part of the active compound but an auxiliary compound of the formulation only. It can be shown, e.g. with gel-permeation chromatography, that the sucrose can be separated completely from the injection solution containing the sodium iron(III)gluconate complex made according to the present invention, without causing any physical change of the sodium iron(III)gluconate complex. According to the present invention, the desired active compound is already entirely formed in solution before precipitation and is precipitated without any change. This further simplifies considerably the subsequent preparation of the injection solution.